The long term goals of this grant are to test mechanisms of pain transmission in the spinal cord of humans and to test whether experimental pain models in animals and humans predict efficacy of spinal analgesics in clinical pain states. We focus on the spinal cord, since this is an important site of regulation of pain transmission and since we can specifically test analgesic mechanisms with spinal injection in the postoperative period and in patients with chronic pain. This grant has in the past examined spinal a2- adrenergic, adenosine, and cholinergic receptors in pain and analgesia, and in the last cycle began the study of spinal prostaglandins, using the cyclooxygenase (COX) inhibitor, ketorolac. Laboratory and clinical studies indicate efficacy of spinal ketorolac for postoperative analgesia by inhibiting COX-1 in spinal microglia which are activated during and after surgery. Our first two specific aims are to: 1. determine in humans the effect of intrathecal ketorolac on mechanical hypersensitivity and pain from surgery and acute systemic opioid exposure 2. determine in animals the key factors interactions which activate COX-1 in spinal microglia and induce pain behaviors from surgery and acute opioid exposure and probe their mechanisms In addition, the last cycle of this grant funded the synthesis of ST91, an a2-adrenoceptor agonist with better efficacy in animal models of acute and chronic pain than clonidine, but without clonidine's hypotensive and sedative side effects. We believe these advantages of ST91 reflect actions on different a2-adrenoceptor subtypes than clonidine. Our last specific aim is to: 3. complete preclinical toxicity screening and chemistry documentation for exploratory investigational new drug application (IND) to the FDA, and perform Phase I safety and efficacy trials in humans The relevance of these studies to public health is to better understand the processes in the human spinal cord which contribute to acute and chronic pain. Not only might this lead to better and safer spinally administered drugs, but these translational studies also provide proof of concept for development of oral drugs to target specific receptors for better and safer pain relief.